Role of PPARγ in the nutritional and pharmacological actions of carotenoids

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to play an important role in the biological effects of carotenoids. The PPAR gamma-signaling pathway is involved in the anticancer effects of carotenoids. Activation of PPAR gamma partly contributes to the growth-inhibitory effects of carotenoids (beta-carotene, astaxanthin, bixin, capsanthin, lutein, and lycopene) on breast cancer MCF7 cells, leukemia K562 cells, prostate cancer (LNCaP, DU145, and PC3 cells), and esophageal squamous cancer EC109 cells. PPAR gamma is the master regulator of adipocyte differentiation and adipogenesis. Downregulated PPAR gamma and PPAR gamma-target genes have been associated with the suppressive effects of beta-carotene and lycopene on 3T3L1 and C3H10T1/2 adipocyte differentiation and adipogenesis. beta-Carotene is cleaved centrally into retinaldehyde by BCO1, the encoding gene being a PPAR gamma-target gene. Retinaldehyde can be oxidized to retinoic acid and also be reduced to retinol. beta-Carotene can also be cleaved asymmetrically into beta-apocarotenals and beta-apocarotenones by BCO2. The inhibitory effects of beta-carotene on the development of adiposity and lipid storage are dependent substantially on BCO1-mediated production of retinoids. The effects of beta-carotene on body adiposity were absent in BCO1-knockout mice. Retinoid metabolism is connected with the activity of PPAR gamma in the control of body-fat reserves. Retinoic acid, retinaldehyde, retinol, and beta-apocarotenals exert suppressive effects on preadipocyte differentiation and adipogenesis via downregulation of PPAR gamma expression in cell culture. The molecular mechanisms underlying retinoic acid effects on adipose-tissue biology and the development of adiposity remain poorly understood. Adiposity can be affected by retinoids through long-lasting effects at critical developmental stages. Retinol saturase increases PPAR gamma-transcriptional activity and adipocyte differentiation. Other carotenoids that have been reported to suppress adipocyte differentiation and lipid accumulation in the main via modulation of PPAR gamma and PPAR gamma-target genes include astaxanthin, bixin, norbixin, beta-cryptoxanthin, fucoxanthin and its metabolites, lycopene, apo-10'-lycopenoic acid, siphonaxanthin, and neoxanthin, except paprika pigments. Lutein, lycopene, and paprika carotenoids reduce proinflammatory cytokine levels by an induction of PPAR gamma in immune tissues and cells. Lycopene, apo-10'-lycopenoic acid, and astaxanthin might prevent atherosclerosis through modifying cholesterol metabolism via increasing PPAR gamma expression in macrophages.